Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Mar 30;72(1):1-5.
doi: 10.2478/aiht-2021-72-3491. Print 2021 Mar 1.

Presence of nitrosamine impurities in medicinal products

Ilijana Sedlo  1 , Teo Kolonić  2 , Siniša Tomić  1   2
Affiliations
Review

Presence of nitrosamine impurities in medicinal products

Ilijana Sedlo et al. Arh Hig Rada Toksikol. .

Abstract
in English, Croatian

In 2018, some sartan medicinal products were reported to be contaminated with nitrosamine compounds, which are potent mutagenic carcinogens. Two nitrosamines received particular attention: N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA). These have since been confirmed in different types of medicinal products, including ranitidine and metformin. Consequently, the European Medicines Agency (EMA) started an investigation into the cause of contamination and an assessment of the risk to patients taking contaminated medicinal products. The main source of contamination were changes in production, which involves combinations of amines and nitrogen compounds and the use of specific catalysts and reagents. Withdrawals of medicinal products that took place in Croatia did not lead to a shortage of sartan- or metformin-containing medicines. Moreover, ranitidine had been preventively withdrawn all over the EU, including Croatia, creating shortages at the time, but was subsequently replaced with therapeutic alternatives.

Nitrozaminski su spojevi jaki kancerogeni i njihova je prisutnost potvrđena 2018. u nekim lijekovima s djelatnom tvari iz skupine sartana. Dva predstavnika nitrozamina, najčešće detektirana kao onečišćenja u lijekovima, jesu N-nitrozodimetilamin (NDMA) i N-nitrozodietilamin (NDEA). Od tada je njihova prisutnost potvrđena u različitim skupinama lijekova, što upućuje na njihovu učestalost. Slijedom toga, Europska agencija za lijekove (EMA) pokrenula je istragu uzroka onečišćenja te procjenu rizika kojima su pacijenti koji su uzimali lijekove onečišćenih serija bili izloženi. Glavni uzrok onečišćenja djelatne tvari uključuje promjene u proizvodnom postupku koji sadržava smjesu amina i dušikovih spojeva uz uporabu specifičnih katalizatora i reagensa. Nitrozamini su također pronađeni u gotovim lijekovima. Povlačenje lijekova u Hrvatskoj nije dovelo do nestašice lijekova koji sadržavaju sartan ili metformin, a lijekovi koji sadržavaju ranitidin povučeni su iz mjera opreza iz ljekarni i u Hrvatskoj i u Europskoj uniji.

Keywords: NDEA; NDMA; carcinogenicity; metformin; ranitidine; sartans.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Production changes that caused formation of NDMA in the Zhejiang Huahai Pharmaceutical plant (6)
Figure 2
Figure 2
Sartans with a tetrazole ring contaminated with impurities (4)
See this image and copyright information in PMC

References

    1. World Health Organization (WHO) Information Note Nitrosamine impurities [displayed 24 September 2020] https://www.who.int/medicines/publications/drugalerts/InformationNote_Ni... Available at.
    1. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) ICH guideline M7(R1) on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk [displayed 7 March 2021] https://www.ema.europa.eu/en/documents/scientific-guideline/ch-guideline... p. 6. Available at.
    1. European Medicines Agency (EMA) Procedure under Article 5(3) of Regulation EC (No) 726/2004. Nitrosamine impurities in human medicinal products [displayed 24 September 2020] https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-... Available at.
    1. European Medicines Agency (EMA) Lessons learnt from presence of N-nitrosamine impurities in sartan medicines [displayed 24 September 2020] https://www.ema.europa.eu/en/documents/report/essons-learnt-presence-n-n... Available at.
    1. Šulc M, Hodek P, Stiborová M. The binding affinity of c a r c in o gen i c N- nit r o so dim et h y l a mine a n d N-nitrosomethylaniline to cytochromes P450 2B4, 2E1 and 3A6 does not dictate the rate of their enzymatic N-demethylation. Gen Physiol Biophys. 2010;29:175–85. doi: 10.4149/gpb_2010_02_175. - DOI - PubMed

LinkOut - more resources